Molecular mechanisms of neurodegeneration related to C9orf72 hexanucleotide repeat expansion

Babić Leko, Mirjana and Župunski, Vera and Kirincich, Jason and Smilović, Dinko and Hortobágyi, Tibor and Hof, Patrick R. and Šimić, Goran (2019) Molecular mechanisms of neurodegeneration related to C9orf72 hexanucleotide repeat expansion. Behavioural Neurology, 2019. pp. 1-18. ISSN 0953-4180

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Abstract

Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2-10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.

Item Type: Article
Additional Information: Copyright © 2019 Mirjana Babić Leko et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Departments: Hrvatski institut za istraživanje mozga
Katedra za neurologiju
Depositing User: Anja Majstorović
Status: Published
Creators:
CreatorsEmail
Babić Leko, MirjanaUNSPECIFIED
Župunski, VeraUNSPECIFIED
Kirincich, JasonUNSPECIFIED
Smilović, DinkoUNSPECIFIED
Hortobágyi, TiborUNSPECIFIED
Hof, Patrick R.UNSPECIFIED
Šimić, GoranUNSPECIFIED
Date: January 2019
Date Deposited: 13 Jun 2019 12:04
Last Modified: 27 Aug 2020 09:22
Subjects: /
Related URLs:
URI: http://medlib.mef.hr/id/eprint/3278

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